This invention relates to cyclic amine phenyl xcex23 adrenergic receptor agonists useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
The subdivision of xcex2 adrenergic receptors (xcex2-AR) into xcex21- and xcex22-AR has led to the development of xcex21- and xcex22-antagonists and/or agonists which have been useful for the treatment of cardiovascular disease and asthma. The recent discovery of xe2x80x9catypicalxe2x80x9d receptors, later called xcex23-AR, has led to the development of xcex23-AR agnoists which may be potentially useful as antiobesity and antidiabetic agents. For recent reviews on xcex23-AR agnoists , see: 1. A. D. Strosberg, Annu. Rev. Pharmacol. Toxicol. 1997, 37, 421; 2. A. E. Weber, Ann. Rep. Med. Chem. 1998, 33, 193; 3. C. P. Kordik and A. B. Reitz, J. Med. Chem. 1999, 42, 181; 4. C. Weyer, J. F. Gautier and E. Danforth, Diabetes and Metabolism, 1999, 25, 11.
Compounds that are potent and selective xcex23 agonists, may be potentially useful antiobesity agents. Low levels or lack of xcex21 and xcex22-agonistic properties will minimize or eliminate the adverse side effects that are associated with xcex21 and xcex22 agonistic activities, i.e. increased heart rate, and muscle tremor, respectively. Early developments in the xcex23-agonist field are described in European patent 427480, U.S. Pat. Nos. 4,396,627, 4,478,849, 4,999,377, and 5,153,210. These early patents purport to claim compounds with greater selectivity for the xcex23-AR than for the xcex21- and xcex22-AR""s. However, clinical trials in humans with such compounds have not been successful to date.
More recently, potent and selective human xcex23 agonists have been described in several patents and published applications: WO 98/32753, WO 97/46556, WO 97/37646, WO 97/15549, WO 97/25311, WO 96/16938, WO 95/29159, European Patents 659737, 801060, 714883, 764640, 827746, and U.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. These compounds were evaluated in Chinese hamster ovary (CHO) cells test procedures which predicts the effects that can be expected in humans. These assays utilize cloned human xcex23 receptors, expressed in CHO cells (see refs. Granneman et al., Mol Pharmacol., 1992, 42, 964; Emorine et al., Science, 1989, 245, 1118; Liggett Mol. Pharmacol., 1992, 42, 634).
xcex23-Adrenergic agonists also are useful in controlling the frequent urge of urination. It has been known that relaxation of the bladder detrusor is under beta adrenergic control (Li J, Yasay G and Kau S. Beta-adrenoceptor subtypes in the detrusor of guinea-pig urinary bladder. Pharmacology 1992; 44: 13-18). Recently, a number of laboratories have provided experimental evidence in a number of animal species including human (Yamazaki Y, Takeda H, Akahane M, Igawa Y, et al. Species differences in the distribution of the beta-adrenoceptor subtypes in bladder smooth muscle. Br. J. Pharmacol. 1998; 124: 593-599) that activation of the xcex23 receptor subtype by norepinephrine is responsible for relaxation of the urinary bladder. Urge urinary incontinence is characterized by abnormal spontaneous bladder contractions that can be unrelated to bladder urine volume. Urge urinary incontinence is often referred to hyperactive or unstable bladder. Several etiologies exist and fall into two major categories, myogenic and neurogenic. The myogenic bladder is usually associated with detrusor hypertrophy secondary to bladder outlet obstruction, or with chronic urinary tract infection. Neurogenic bladders are associated with an uninhibited micturition reflex. An upper motor neuron disease is usually the underlying cause. In either case, the disease is characterized by abnormal spontaneous contractions that result in an abnormal sense of urinary urgency and involuntary urine loss. At present, the most common therapy for hyperactive bladder includes the use of antimuscarinic agents to block the action of the excitatory neurotransmitter acetylcholine. While effective in neurogenic bladders, their utility in myogenic bladders is questionable. In addition, due to severe dry mouth side-effects associated with antimuscarinic therapy, the patient compliance with these agents is only approximately 30%.
In the bladder, xcex23 adrenergic receptor agonists activate adenylyl cyclase and generate cAMP through the G-protein coupled xcex23 receptor. The resulting phosphorylation of phospholamban/calcium ATPase enhances uptake of calcium into the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits bladder smooth muscle contractility.
It is suggested therefore, that activation of the xcex23 adrenergic receptor in the urinary bladder will inhibit abnormal spontaneous bladder contractions and be useful for the treatment of bladder hyperactivity. Note, that unlike the antimuscarinics, xcex23 adrenergic receptor agonists would be expected to be active against both neurogenic and myogenic etiologies.
Despite all these recent developments there is still no single therapy available for the treatment of type II diabetes (NIDDM), obesity, atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, frequent urination and related diseases. A potent and selective xcex23 adrenergic receptor agonist is therefore highly desirable for the potential treatment of such disease states.
This invention provides compounds of Formula I having the structure 
wherein
A is Ar or Het;
X is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, or a bond;
T1 is (CH2)m;
T2 is (CH2)n;
T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms;
R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, dihydroxyphosphorylamino, xe2x80x94CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
R4 is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms, ArCO-, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbon atoms,
R5 is 
Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5; or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
Y and Z are each, independently, NR7, O, or S;
X1 and X2 are each, independently, CO or SO2;
a dotted line represents and optional double bond;
R6, R7, and R8 are each, independently, hydrogen; alkyl of 1-6 carbon atoms optionally substituted by R11, R12, and R13; alkenyl of 2-7 carbon atoms op tionally substituted by R11, R12, and R13; alkynyl of 2-7 carbon atoms optionally substituted with R11; cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12, and R13; bicycloalkyl of 7-11 carbon atoms optionally substituted by R11, R12, and R13; xe2x80x94CO2-alkyl of 1-6 carbon atoms; Het optionally substituted by R11, R12, or R13; or Ar optionally substituted by R11, R12, and R13; or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
R9 and R10 are each, independently, alkyl optionally substituted by R11, R12, and R13; Ar optionally mono-, di-, or tri-substituted by R15; Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, or tri-substituted by R15; Het optionally mono-, di-, or tri-substituted by R15;
R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CO2H, xe2x80x94OCO2-alkyl of 1-6 carbon atoms, xe2x80x94CO2-alkyl of 1-6 carbon atoms, xe2x80x94CO2xe2x80x94Ar, xe2x80x94CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, xe2x80x94OCO2xe2x80x94Ar, xe2x80x94CONH2, xe2x80x94CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, xe2x80x94NHCONH-alkyl of 1-6 carbon atoms, xe2x80x94NHSO2-alkyl of 1-6 carbon atoms, xe2x80x94NHSO2xe2x80x94Ar, or xe2x80x94NHSO2-Het; or when R11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, xe2x80x94SO2-alkyl of 1-6 carbon atoms, xe2x80x94CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
R15 is
(a) hydroxy, halogen, xe2x80x94CN, xe2x80x94NR16R16, xe2x80x94OR16, xe2x80x94SR16, triflouromethyl, alkyl of 1-6 carbon atoms, xe2x80x94SO2R17, xe2x80x94O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, xe2x80x94CO2R17, xe2x80x94OCOR17, xe2x80x94NR16COR17, xe2x80x94COR17, xe2x80x94NR16SO2R17, or xe2x80x94NR16CO2R16; or
(b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy; halogen; xe2x80x94CN; xe2x80x94NR16NR16; xe2x80x94OR16; xe2x80x94SR16; triflouromethyl; alkyl of 1-6 carbon atoms; xe2x80x94SO2R17; xe2x80x94CO2R17; xe2x80x94OCOR17; xe2x80x94NR16COR17; xe2x80x94COR17; xe2x80x94NR16SO2R17; xe2x80x94NR16CO2R16; Ar which may be optionally mono- or di-substituted by R16, xe2x80x94OR16, xe2x80x94NR16R16, or halogen; or Het which may be optionally mono- or di-substituted by R16, xe2x80x94OR16, xe2x80x94NR16R16, or halogen;
(c) Het optionally mono- or di-substituted by R16, xe2x80x94OR16, xe2x80x94NR16R16, or halogen; or
(d) Ar optionally mono- or di-substituted by R16, xe2x80x94OR16, xe2x80x94NR16R16, or halogen;
R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, xe2x80x94CO2H, xe2x80x94CO2alkyl of 1-6 carbon atoms, or xe2x80x94SO2alkyl of 1-6 carbon atoms;
R17 is R16 or xe2x80x94NR16R16;
Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein the heterocycle may be saturated, unsaturated, or partially unsaturated; and may be optionally fused to a phenyl ring;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
m=1-3;
n=1-3;
or a pharmaceutically acceptable salt thereof, which are selective agonists at human xcex23 adrenergic receptors and are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, such as alkali metal salts (for example, sodium, lithium, or potassium), alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acidic moiety.
The compounds of the instant invention all contain at least one asymmetric center. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, are included within the scope of the instant invention. Any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials of know configuration.
The compounds of the present invention may also contain geometric isomers. Thus, the present invention includes all individual isomers and mixtures thereof.
Alkyl, alkenyl, and alkynyl include both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine. Where a substituent contains one or more moieties which have the same designation, each of the moieties can be the same or different. Ar and the term xe2x80x9carylxe2x80x9d includes monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl. Benzyl is the preferred arylalkyl moiety.
Preferred Het moieties include: (a) 6-membered saturated, partially unsaturated, or unsaturated heterocycles containing 1-2 nitrogens, optionally fused to a phenyl ring; (b) 5-membered saturated, partially saturated, or unsaturated heterocycles containing 1-3 nitrogen, oxygen, or sulfur atoms, optionally fused to a phenyl ring; (c) saturated, partially unsaturated, or unsaturated bicyclic heterocycles containing 1-4 nitrogen, oxygen, or sulfur atoms; (d) carbazole, dibenzofuran, and dibenzothiophene. In the Het of categories (a), (b), and (c), ring carbon atoms may be carbonyl moieties, where the ring does not contain a double bond in that position (for example, thiazolidine-2,4-dione).
More preferred Het rings include pyrrole, furan, thiophene, imidazole, pyrazole, furazan, triazole, tetrazole, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, 1,3,5-triazine, 1,2,4,5-tetrazine, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzimidazol, 3H-benzoxazol-2-one, benzotriazole, quinoline, isoquinoline, quinazoline, indazole, 1 H-quinolin-2-one, 3,4-dihydro-1H-quinolin-2-one, 2,3-dihydro-1H-indole, 1,3-dihydro-benzoinimidazol-2-thione, carbazole, 3,5-dioxo-[1,2,4]oxadiazolidine, 2,4-dioxo-3-thiazolidine, 1H-benzoimidazole, 2-thioxo-thiazolidin-4-one, 2-imino-4-oxo-thiazolidine, 2-oxo-1,2,3,4-tetrahydro-quinoline, 2,4-dioxo-thiazolidine, 5-oxo-2,5-dihydro-1H-pyrazole, 2-oxo-2,3-dihydro-1H-benzimidazole, 9H-carbazole, benzothiophene, morpholine, piperidine, and 1,3-benzodioxole. It is understood that Het do not contain heteroatoms in arrangements which would make them inherently unstable. For example, the term Het does not include ring systems containing Oxe2x80x94O bonds in the ring backbone.
Preferred amino acids include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, xcex2-alanine, cyclopropane amino acids (such as 1-aminocyclopropane-1-carboxylic acid, allo-coronamic acid and 2,3-methanohomoserine), 1-aminocyclohexane-1-carboxylic acid, isonipecotic acid, 2-azetidinecarboxylic acid, and esters thereof.
Preferred compounds of Formula I are those in which
A is Ar or Het;
X is xe2x80x94OCH2xe2x80x94 or a bond;
T1 is (CH2)m;
T2 is (CH2)n;
T is a bond, alkyl of 1-6 carbon atoms optionally substituted with R11, alkenyl of 2-7 carbon atoms optionally substituted with R11, or alkoxyalkyl of 1-6 carbon atoms per alkyl moiety;
R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, xe2x80x94CO2-alkyl of 1-6 carbon atoms, or Ar optionally substituted with R11;
R4 is hydrogen or halogen;
R5 is 
Aa is (i) an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5; or (ii) an alkyl ester of an amino acid, wherein the nitrogen of amino acid attached to the adjacent carbonyl of R5, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
Y and Z are each, independently, NR7, O, or S;
X1 and X2 are each, independently, CO or SO2;
a dotted line represents and optional double bond;
R6, R7, and R8 are each, independently, hydrogen; alkyl of 1-6 carbon atoms optionally substituted by R11, R12, and R13; cycloalkyl of 3-8 carbon atoms optionally substituted by R11, R12, and R13; bicycloalkyl of 7-11 carbon atoms optionally substituted by R11, R12, and R13; xe2x80x94CO2-alkyl of 1-6 carbon atoms; Het optionally substituted by R11, R12, or R13; or Ar optionally substituted by R11, R12, and R13; or when R6 and R7 are contained on a common nitrogen, they may be taken together to form a saturated 5-7 membered heterocycle that is optionally substituted with R11;
R9 and R10 are each, independently, alkyl optionally substituted by by R11, R12, and R13; Ar optionally mono-, di-, or tri-substituted by R15; Het optionally mono-, di-, or tri-substituted by R15;
R11, R12, or R13 are each, independently, alkyl of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Ar optionally substituted with R14, Het optionally substituted with R14, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CO2H, xe2x80x94OCO2-alkyl of 1-6 carbon atoms, xe2x80x94CO2-alkyl of 1-6 carbon atoms, xe2x80x94CO2xe2x80x94Ar, xe2x80x94CO2-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms, xe2x80x94OCO2xe2x80x94Ar, xe2x80x94CONH2, xe2x80x94CONHOH, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, xe2x80x94NHCONH-alkyl of 1-6 carbon atoms, xe2x80x94NHSO2-alkyl of 1-6 carbon atoms, xe2x80x94NHSO2xe2x80x94Ar, or xe2x80x94NHSO2-Het; or when R11 and R12 are contained on a common carbon atom of an alkyl moiety, they may be taken together to form a spiro cycloalkyl ring of 3-8 carbon atoms;
R14 is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, hydroxy, acyl of 2-7 carbon atoms, xe2x80x94SO2-alkyl of 1-6 carbon atoms, xe2x80x94CO2-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms;
R15 is
(a) halogen, xe2x80x94CN, xe2x80x94OR16, triflouromethyl, alkyl of 1-6 carbon atoms, xe2x80x94SO2R17, xe2x80x94O-alkyl-CO2R17 wherein the alkyl moiety contains 1-6 carbon atoms, xe2x80x94CO2R17, xe2x80x94NR16COR17, xe2x80x94COR17; or
(b) alkyl of 1-6 carbon atoms mono-, or di-substituted with halogen; xe2x80x94NR16COR17; Ar which may be optionally mono- or di-substituted by R16, xe2x80x94OR16, xe2x80x94NR16R16, or halogen; or Het which may be optionally mono- or di-substituted by R16, xe2x80x94OR16, xe2x80x94NR16R16, or halogen;
(c) Het optionally mono- or di-substituted by R16, OR16, xe2x80x94NR16R16, or halogen; or
(d) Ar optionally mono- or di-substituted by R16, OR16, xe2x80x94NR16R16, or halogen;
R16 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-, or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, xe2x80x94CO2H, xe2x80x94CO2alkyl of 1-6 carbon atoms, or xe2x80x94SO2alkyl of 1-6 carbon atoms;
R17 is R16 or xe2x80x94NR16R16;
Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein the heterocycle may be saturated, unsaturated, or partially unsaturated; and may be optionally fused to a phenyl ring;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;
m=1-2;
n=1-2;
or a pharmaceutically acceptable salt thereof.
Specifically preferred compounds of this invention are:
a) N-[5-((1R)-2-{1-[4-(3,5-dioxo-[1,2,4]oxadiazolidin-2-ylmethyl)-phenyl]-piperidine-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;
b) 5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidineyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineacetic acid tert-butyl-ester;
c) 5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidineyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineacetic acid;
d) 5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidineyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineacetic acid ethyl-ester;
e) 5-(3-fluoro-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidine-1-yl}-benzyl)-thiazolidine-2,4-dione;
f) 5-(3-bromo-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidine-1-yl}-benzylidene)-thiazolidine-2,4-dione;
g) 5-(3-fluoro-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidine-1-yl}-benzylidene)-thiazolidine-2,4-dione;
h) N-[5-(2-{1-[2-bromo-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;
i) N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenyl]-piperidine-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;
j) 5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidine-1-yl]-benzylidene}-2-thioxo-thiazolidin-4-one;
k) 5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidine-1-yl]-benzyl}-thiazolidin-2,4-dione;
l) 5-(4-{4-[(2S)-3-(4-benzyloxy-phenoxy)-2-hydroxy-propylamino]-piperidine-1-}-benzyl)-thiazolidine-2,4-dione;
m) 5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidine-1-yl}-benzylidene)-thiazolidine-2,4-dione;
n) 5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidine-1-yl}-benzylidene)-thiazolidine-2,4-dione;
o) N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;
p) N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidine-4-ylamino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;
q) 5-(4-{4-[2-(3-chloro-phenyl)-(2R)-2-hydroxyethylamino}-piperidine-1-yl}-benzyl)-thiazolidine-2,4-dione;
r) 5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidine-1-yl}-benzyl)-thiazolidine-2,4-dione;
s) 5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidine-1-yl}-benzyl)-thiazolidine-2,4-dione;
t) 5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidine-1-yl}-benzylidene)-2-thioxo-thiazolidin-4-one;
u) 5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidine-1-yl]-benzylidene}-thiazolidine-2,4-dione;
v) N-[5-((2R)-2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidine-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;
w) N-[5-(2-{1-[4-(2,5-dioxo-imidazolidin-4-ylidenemethyl)-phenyl]-piperidine-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;
x) 5-(4-{4-[2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidine-1-yl}-benzyl)-imidazolidine-2,4-dione-piperidine-1-yl}-benzyl)-imidazolidine-2,4-dione;
y) N-[5-(2-{1-[4-(2,5-dioxo-imidazolidin-4-ylmethyl)-phenyl]-piperidine-4-ylamino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;
z) N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;
aa) 4-((2S)-2-hydroxy-3-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidine-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;
bb) N-[2-hydroxy-5-(1-hydroxy-2-(1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidine-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;
cc) 5-(4-{4-[(2S)-2-hydroxy-3-(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-5-yloxy)-propylamino]-piperidine-1-yl}-benzyl)-thiazolidine-2,4-dione;
dd) N-[5-((2S)-3-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidine-4-ylamino}-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide;
ee) N-[5-((2S)-3-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]- piperidine-4-ylamino}-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide;
ff) (R)-propane-2-sulfonic acid [5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidine-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide;
gg) N-[2-chloro-5-((1R)-2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidine-4-ylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;
hh) N-(5-{(1R)-2-[(1-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}piperidine-4-yl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)benzenesulfonamide;
ii) N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(1H-tetrazol-5-yl)-phenyl]-piperidine-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;
jj) ethyl [5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-1H-tetraazol-1-yl]acetate;
kk) [5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-1H-tetraazol-1-yl]acetic acid;
ll) [5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-2H-tetraazol-2-yl]acetic acid;
mm) 5-{4-[4-({(2S)-2-hydroxy-2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]ethyl}amino)piperidine-1-yl]benzyl}-1,3-thiazolidine-2,4-dione;
nn) 5-{4-[4-({(2S)-2-[3-(3,4-dichlorophenyl)isoxazol-5-yl]-2-hydroxyethyl}amino)piperidine-1-yl}benzyl}-1,3-thiazole-2,4-dione;
oo) N-(4-{(1R)-2-[(1-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}piperidine-4yl)amino]-1-hydroxyethyl)}phenyl)methanesulfonamide;
pp) 5-[4-(4-{[4-(2S)-2-(3-bromoisoxazol-5-yl)-2-hydroxyethyl]amino}piperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione;
qq) 5-(4-{4-[(2S)-2-hydroxy-3-(pyridin-3-yloxy)-propylamino]-piperidine-1-yl}-benzyl)-thiazolidine-2,4-dione;
rr) 5-(4-{4-[(2S)-2-hydroxy-3-(6-methyl-pyridin-3-yloxy)-propylamino]-piperidine-1-yl}-benzyl)-thiazolidine-2,4-dione;
ss) 5-{4-[4-((2S)-2-hydroxy-2-pyridin-3-yl-ethylamino)-piperidine-1-yl]- benzyl}-thiazolidine-2,4-dione;
tt) 5-(4-{4-[(2S)-2-(6-amino-pyridin-3-yl)-2-hydroxy-ethylamino]-piperidine-1-yl}-benzyl)-thiazolidine-2,4-dione hydrochloride;
uu) 5-{4-[4-((2R)-2-hydroxy-2-pyridin-3-yl-ethylamino)-piperidine-1-yl]-benzyl}-thiazolidine-2,4-dione;
vv) N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidine-4-ylamino}-1-hydroxy-ethyl)-pyridin-2-yl]-methanesulfonamide;
ww) 5-(3-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-2-fluoro-phenyl]-piperidine-4-ylamino}-(2S)-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylic acid ethyl ester;
xx) N-[(2R)-2-hydroxy-5-(1-hydroxy-2-{1-[4-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-phenyl]-piperidine-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;
yy) 4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidine-1-yl}-benzoic acid ethyl ester;
zz) {4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoic acid ethyl ester;
aaa) {4-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-piperidine-1-yl}-benzoic acid ethyl ester hydrochloride;
bbb) (4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-phenyl)-acetic acid;
ccc) 3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-phenyl)-acrylic acid ethyl ester;
ddd) 3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-phenyl)-propionic acid;
eee) (4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzyloxy)-acetic acid;
fff) 4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoic acid;
ggg) 3-(4-(4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-phenyl)-propionic acid ethyl ester;
hhh) 2-(4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzylidene)-malonic acid diethyl ester;
iii) 2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzylidene)-malonic acid monoethyl ester;
jjj) 4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzamide;
kkk) N-benzyloxy-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzamide;
lll) diethyl (2S)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}benzoyl)amino]pentanedioate;
mmm) ethyl 3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}benzoyl)amino]propanoate;
nnn) (2S)-2-[(4-{4-[((2R)-2-hydroxy-2-(4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}benzoyl)amino]pentanedioic acid;
ooo) N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}benzoyl)-beta-alanine;
ppp) ethyl [(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}benzoyl)amino]acetate;
qqq) [(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}benzoyl)amino]acetic acid;
rrr) (2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoylamino)-4-methyl-pentanoic acid ethyl ester;
sss) (2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoylamino)-4-methyl-pentanoic acid;
ttt) 1-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoyl)-pyrrolidine-(2S)-2-carboxylic acid methyl ester;
uuu) 1-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoyl)-pyrrolidine-(2S)-2-carboxylic acid;
vvv) (2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoylamino)-3-methyl-butyric acid ethyl ester;
www) (2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoylamino)-3-methyl-butyric acid;
xxx) (2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoylamino)-3-phenyl-propionic acid methyl ester;
yyy) (2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoylamino)-3-phenyl-propionic acid;
zzz) methyl 1-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-piperidineyl}benzoyl)amino]cyclopropanecarboxylate;
aaaa) [butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoyl)-amino]-acetic acid ethyl ester;
bbbb) methyl [(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}benzoyl)amino]acetate;
cccc) (2S)-2-(4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoylamino)-4-methyl-pentanoic acid methyl ester;
dddd) (2E)-3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-phenyl)-acrylic acid;
eeee) 4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzamide;
ffff) 4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-sulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}-N-[(3S)-2-l}ethyl)amino]-1-piperidineyl}-N-[(3S)-2-oxoazepanyl]benzamide;
gggg) N-butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}-N-(1H-tetraazol-5-ylmethyl)benzamide.
hhhh) N-{4-[4-(2-hydroxy-2-phenyl-ethylamino)-piperidine-1-yl]-phenyl}-4-methoxy-benzenesulfonamide;
iiii) N-(4-{4-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidine-1-yl}-phenyl)-4-methoxy-benzenesulfonamide;
jjjj) N-[4-(4-{4-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidine-1-yl}-phenylsulfamoyl)-phenyl]-acetamide;
kkkk) N-(4-{4-[4-((2R)-2-hydroxy-2-phenyl-ethylamino)-piperidine-1-yl]-phenylsulfamoyl}-phenyl)-acetamide;
llll) N-(4-{[4-(4-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
mmmm) N-[4-(4-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-1-piperidineyl)phenyl]-4-methoxybenzenesulfonamide;
nnnn) N-[4-(4-{[(2R)-2-hydroxy-2-phenylethyl]amino}-1-piperidineyl)phenyl]-4-methoxybenzenesulfonamide;
oooo) N-(4-{[4-(4-{[2-hydroxy-3-(4-methoxyphenoxy)propyl]amino}-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
pppp) N-(4-{[4-(4-{[(2R)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
qqqq) N-(4-{[2-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
rrrr) N-(4-{[2-(4-{[(2R)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
ssss) N-[4-(4-{[(2R)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino-1-piperidineyl)phenyl]-4-methoxybenzenesulfonamide;
tttt) N-(4-{[4-(4-{[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]amino}-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
uuuu) N-(4-{[4-(4-{[2-(2,4-dihydroxyphenyl)-2-hydroxyethyl]amino-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
vvvv) N-(4-{[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
wwww) N-{4-[(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]phenyl}acetamide;
xxxx) 4-{[(hexylamino)carbonyl]amino}-N-[4-(4-{[2-hydroxy-2-(6-methyl-3-pyridinyl)ethyl]amino}-1-piperidineyl)phenyl]benzenesulfonamide;
yyyy) N-(4-{[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
zzzz) 5-[2-({1-[4-({[4-(acetylamino)phenyl]sulfonyl}amino)phenyl]-4-piperidineyl}amino)-1-hydroxyethyl]-1H-indole-7-carboxamide;
aaaaa) N-[4-({4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]anilino}sulfonyl)phenyl]acetamide;
bbbbb) 4-{[(hexylamino)carbonyl]amino}-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
ccccc) 4-{[(hexylamino)carbonyl]amino}-N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)benzenesulfonamide;
ddddd) 4-[4-(3-cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-tetraazol-1-yl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
eeeee) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-5-(2-pyridinyl)-2-thiophenesulfonamide;
fffff) N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidineyl)phenyl]-3,4-dimethoxybenzenesulfonamide;
ggggg) N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-3,4-dimethoxybenzenesulfonamide;
hhhhh) 4-butoxy-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)benzenesulfonamide;
iiiii) N-(4-{[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidineyl)anilino]sulfonyl}phenyl)acetamide;
jjjjj) 5-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-3-methyl-1-benzothiophene-2-sulfonamide;
kkkkk) 4-cyano-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
lllll) 4-cyano-N-[(4-cyanophenyl)sulfonyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
mmmmm) 3-bromo-5-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-2-thiophenesulfonamide;
nnnnn) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-5-(3-isoxazolyl)-2-thiophenesulfonamide;
ooooo) 4-[4-(3-cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-tetraazol-1-yl]-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)benzenesulfonamide;
ppppp) 4-butoxy-N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidineyl)phenyl]benzenesulfonamide;
qqqqq) N-[4-(4-{[3-(9H-carbazol-4-yloxy)-(2S)-2-hydroxypropyl]amino}-1-piperidineyl)phenyl]-4-{[(hexylamino)carbonyl]amino}benzenesulfonamide;
rrrrr) N-{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]phenyl}acetamide;
sssss) N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidineyl)phenyl]-3,4-dimethoxybenzenesulfonamide;
ttttt) N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidineyl)phenyl]-5-(2-pyridinyl)-2-thiophenesulfonamide;
uuuuu) N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-5-(2-pyridinyl)-2-thiophenesulfonamide;
vvvvv) N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-1-butanesulfonamide;
wwwww) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-1-butanesulfonamide;
xxxxx) N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-1-octanesulfonamide;
yyyyy) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-1-octanesulfonamide;
zzzzz) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-5-{[5-(trifluoromethyl)-2-pyridinyl]sulfonyl}-2-thiophenesulfonamide;
aaaaaa) N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidineyl)phenyl]-5-{[5-(trifluoromethyl)-2-pyridinyl]sulfonyl}-2-thiophenesulfonamide;
bbbbbb) 4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
cccccc) 4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)benzenesulfonamide;
dddddd) N-{4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidineyl]phenyl}-3,4-dimethoxybenzenesulfonamide;
eeeeee) N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidineyl)phenyl]-1-octanesulfonamide;
ffffff) 4-{[(hexylamino)carbonyl]amino}-N-{4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
gggggg) N-{4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidineyl]phenyl}-1-butanesulfonamide;
hhhhhh) N-[4-({4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidineyl]anilino}sulfonyl)phenyl]acetamide;
iiiiii) N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidineyl}phenyl)-,4-dimethoxybenzenesulfonamide;
jjjjjj) N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidineyl}phenyl)-1-butanesulfonamide;
kkkkkk) 4-{[(hexylamino)carbonyl]amino}-N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidineyl}phenyl)benzenesulfonamide;
llllll) N-[4-(4-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-1-piperidineyl)phenyl]-4-{[(hexylamino)carbonyl]amino}benzenesulfonamide;
mmmmmm) ethyl {4-[(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidineyl}anilino)sulfonyl]phenyl}acetate;
nnnnnn) methyl {4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]phenoxy}acetate;
oooooo) methyl [4-({4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]anilino}sulfonyl)phenoxy]acetate;
pppppp) N-[5-({(2S)-3-[(1-{4-[(butylsulfonyl)amino]phenyl}-4-piperidineyl)amino]-2-hydroxypropyl}oxy)-2-hydroxyphenyl]benzenesulfonamide;
qqqqqq) N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(isopropylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-1-butanesulfonamide;
rrrrrr) 4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]benzoic acid;
ssssss) ethyl 4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]benzoate;
tttttt) methyl {4-[(4-{4-[((2R)-2-{4-chloro-3-[(methylsulfonyl)amino]phenyl}-2-hydroxyethyl)amino]-1-piperidineyl}anilino)sulfonyl]phenoxy}acetate;
uuuuuu) methyl 3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]-2-thiophenecarboxylate;
vvvvvv) 3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]-2-thiophenecarboxylic acid;
wwwwww) benzyl [(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]acetate;
xxxxxx) [(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]acetic acid;
yyyyyy) benzyl [(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]acetate;
zzzzzz) [(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]acetic acid;
aaaaaaa) N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-3-pyridinesulfonamide;
bbbbbbb) 3,4-dichloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
ccccccc) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-4-(trifluoromethyl)benzenesulfonamide;
ddddddd) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-4-(trifluoromethoxy)benzenesulfonamide;
eeeeeee) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-4-methoxybenzenesulfonamide;
fffffff) 4-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
ggggggg) 4-butyl-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
hhhhhhh) 3,5-dichloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
iiiiiii) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-2,5-dimethoxybenzenesulfonamide;
jjjjjjj) N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-2,5-dimethoxybenzenesulfonamide;
kkkkkkk) ethyl {[(4-butylphenyl)sulfonyl]-4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]anilino}acetate;
lllllll) 5-bromo-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-2-methoxybenzenesulfonamide;
mmmmmmm) 5-bromo-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-2-methoxybenzenesulfonamide;
nnnnnnn) ethyl ([(3,4-dimethoxyphenyl)sulfonyl]-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)acetate;
ooooooo) ethyl 5-[((2S)-3-{[1-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-4-piperidineyl]amino}-2-hydroxypropyl)oxy]-2-methyl-1H-indole-3-carboxylate;
ppppppp) ethyl 4-[((2S)-3-{[1-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-4-piperidineyl]amino}-2-hydroxypropyl)oxy]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate;
qqqqqqq) benzyl ((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)acetate;
rrrrrrr) ((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)acetic acid;
sssssss) ([(3,4-dimethoxyphenyl)sulfonyl]-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)acetic acid;
ttttttt) ethyl ((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)acetate;
uuuuuuu) 4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidineyl)phenyl]benzenesulfonamide;
vvvvvvv) N-{[5-({4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]anilino}sulfonyl)-2-thienyl]methyl}benzamide;
wwwwwww) N-[(5-{[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidineyl)anilino]sulfonyl}-2-thienyl)methyl]benzamide;
xxxxxxx) N-[(5-{[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidineyl)anilino]sulfonyl}-2-thienyl)methyl]benzamide;
yyyyyyy) 4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
zzzzzzz) 4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidineyl)phenyl]benzenesulfonamide;
aaaaaaaa) 3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
bbbbbbbb) 3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidineyl)phenyl]benzenesulfonamide;
cccccccc) 3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidineyl)phenyl]benzenesulfonamide;
dddddddd) N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidineyl)phenyl]-2-thiophenesulfonamide;
eeeeeeee) 4-butoxy-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidineyl)phenyl]benzenesulfonamide;
ffffffff) N-[4-(4-{[(2S)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidineyl)phenyl]-2-thiophenesulfonamide;
gggggggg) 4-butoxy-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}benzenesulfonamide;
hhhhhhhh) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-3,4-dimethoxybenzenesulfonamide;
iiiiiiii) N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidineyl)phenyl]-3,4-dimethoxybenzenesulfonamide;
jjjjjjjj) N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidineyl)phenyl]-3,4-dimethoxybenzenesulfonamide;
kkkkkkkk) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-2-thiophenesulfonamide;
llllllll) ethyl 3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)-3-oxopropanoate;
mmmmmmmm) 3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)-3-oxopropanoic acid;
nnnnnnnn) ethyl 3-(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)-3-oxopropanoate;
oooooooo) 3-(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)-3-oxopropanoic acid;
pppppppp) ethyl 3-(cyclohexyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)-3-oxopropanoate;
qqqqqqqq) 3-(cyclohexyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)-3-oxopropanoic acid;
rrrrrrrr) ethyl {[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)carbonyl]amino}acetate;
ssssssss) {[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)carbonyl]amino}acetic acid;
tttttttt) ethyl {[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)carbonyl]amino}acetate;
uuuuuuuu) {[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)carbonyl]amino}acetic acid;
vvvvvvvv) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-3,4-dimethoxybenzamide;
wwwwwwww) 2-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}acetamide;
xxxxxxxx) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-2-(4-morpholinyl)acetamide;
yyyyyyyy) 2-(dimethylamino)-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}acetamide;
zzzzzzzz) N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-3,4-dimethoxybenzamide;
aaaaaaaaa) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}butanamide;
bbbbbbbbb) N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidineyl)phenyl]butanamide;
ccccccccc) N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidineyl)phenyl]-3,4-dimethoxybenzamide;
ddddddddd) N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidineyl)phenyl]-3,4-dimethoxybenzamide;
eeeeeeeee) N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}-1,3-benzodioxole-5-carboxamide;
fffffffff) N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidineyl)phenyl]-1,3-benzodioxole-5-carboxamide;
ggggggggg) 3-cyclopentyl-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidineyl]phenyl}propanamide;
hhhhhhhhh) 3-cyclopentyl-N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)propanamide;
iiiiiiiii) N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-1,3-benzodioxole-5-carboxamide;
jjjjjjjjj) N-acetyl-N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]acetamide;
kkkkkkkkk) 4-butoxy-N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]benzenesulfonamide;
lllllllll) N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;
mmmmmmmmm) N-(4-{[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)anilino]sulfonyl}phenyl)acetamide;
nnnnnnnnn) 4-butoxy-N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]benzenesulfonamide;
ooooooooo) N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]acetamide;
ppppppppp) N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;
qqqqqqqqq) N-(4-{[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)anilino]sulfonyl}phenyl)acetamide
or a pharmaceutically acceptable salt thereof.
The compounds of this invention can be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention.
According to one route (Scheme 1), 1,4-dioxa-8-azaspiro[4.5]decane is reacted with 4-fluorobenzaldehyde 1 in the presence of base such as pyridine or potassium carbonate to afford aldehyde 2. This reaction can be carried out in a polar solvent such as anhydrous acetonitrile, acetone, N,N-dimethylformamide, or pyridine. Compound 4 is obtained via a Knoevenagel condensation between an appropriate cyclic lactam 3 and the aldehyde 2. In this reaction sodium acetate, p-alanine, glycine, pyridine, piperidine, pyrrolidine, sodium methoxide, potassium acetate, sodium carbonate and the like can be used as a base, and an alcohol such as methanol, ethanol, isopropanol, methoxyethanol and the like, N,N-dimethylformamide, water, acetic acid and the like can be used as a solvent. Ketal hydrolysis is accomplished in the presence of strong acid such as concentrated hydrochloric acid or 10-30% sulfuric acid. The desired final product 7, wherein A, R1, R2, R3, R4, R6, X, Y and Z are as defined above, is prepared by utilizing reductive amination of piperidione 5 with appropriate arylethanolamines or aryloxypropanolamines 6, many of which are comercially available or can be readily prepared as described in Scheme 19 and Scheme 20. The reductive amination can be carried out, for example, with hydrogen and catalytic palladium, or with sodium borohydride, sodium triacetoxyborohydride and the like in a polar solvent such as methanol, N,N-dimethylformamide and the like. The final products can be purified by recrystallization, trituration, preparative thin layer chromatography, flash column chromatography on silica gel, or high performance liquid chromatography. Purification of intermediates can be achieved in the same manner. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
In some cases the Cxe2x80x94C double bond of compound 4 can be reduced (Scheme 2) by catalytic hydrogenation in the presence of a metal catalyst such as palladium, platinum, rhodium and the like. An alcohol such as methanol, ethanol, isopropanol and the like, acetic acid, tetrahydrofuran (THF), dioxane and the like can be used as a solvent in the hydrogenation. In other cases, owing to the presence of sulfur in the molecule, the Cxe2x80x94C double bond of compound 4 can not be reduced by ordinary catalytic hydrogenation. However, the reduction can be achieved by a hydrogen transfer reaction using 3-10% sodium mercury amalgam, zinc, dihydropyridine, tin and the like as a hydrogen donor. In this reaction THF/water, acetic acid, toluene, ethanolic hydrogen iodide and the like can be used as a solvent. Ketal hydrolysis under acidic conditions followed by reductive amination, as previously described in Scheme 1, furnishes the desired final product 10, wherein A, R1, R2, R3, R4, X, Y and Z are as defined above (Scheme 2). A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid.
Compound 9 could be optionally alkylated with an appropriate alkylating agents R6-halo in the presence of base to give the alkylated compound 11 (Scheme 2). At this time, bases to be used include cesium carbonate, potassium carbonate, sodium carbonate, sodium acetate, potassium acetate and the like. Solvents used include N,N-dimethylformamide, acetone, acetonitrile and the like. A reductive amination between ketone 11 and amine 6 , as previously described in Scheme 1, furnishes the final product 12, wherein A, R1, R2R3, R4, R6, X, Y and Z are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
The compound represented by the above formula I wherein R5 is tetrazole can be prepared by one of the following synthetic schemes (Scheme 3 and Scheme 4). Nitrile compound 14 can be obtained by condensing 1,4-dioxa-8-azaspiro[4.5]decane with 4-fluorobenzonitrile as previously described in Scheme 1. The reaction for the formation of the tetrazoles can be carried out by reacting nitriles 14 with sodium azide, tributyltin azide and the like in the presence of an amine salt such as ammonium chloride, triethylamine hydrochloride, diethylamine hydrochloride, tripropylamine hydrosulfate and the like. Solvents used in this reaction include aromatic hydrocarbons such as toluene, xylene, benzene, nitrobenzene and the like. Sometimes the cycloaddition can also be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide and the like. Ketal hydrolysis under acidic conditions followed by reductive amination, as previously described in Scheme 1, furnishes the final product 17 (Scheme 3), wherein A, R1, R2, R3, R4 and X are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
Tetrazole 15 could be optionally alkylated with an appropriate alkylating agents R6-halo in the presence of base such as cesium carbonate to give a pair of isomers (18 and 19) which could be separated by flash column chromatography on silica gel. Ketal hydrolysis under acidic conditions followed by reductive amination, as previously described in Scheme 1, furnishes the final products 22 or 23, wherein A, R1, R2, R3, R4, R6 and X are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
The compound represented by the above formula I wherein R5 is oxadiazolidine can be prepared by the following synthetic scheme (Scheme 5). Compound 24 is obtained by a reductive amination reaction between aldehyde 2 and hydroxylamine. This reductive amination can be carried out essentially under the same conditions as that previously described in Scheme 1. N-Hydroxyurea 25 is obtained by reacting compound 24 with isocyanate such as chlorocarbonyl isocanate, trimethylsilyl isocyanate and the like, followed by ketal hydrolysis. In the isocyanate reaction a polar solvent such as 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide and the like can be used as a solvent. Ketal hydrolysis is conveniently conducted under acidic conditions as that previously described in Scheme 1. The oxadiazolidine ring is formed by reacting the N-hydroxyurea 25 with chloroformate such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate and the like in the presence of strong base such as sodium hydride, potassium hydroxide and the like. The final product 27, wherein A, R1, R2, R3, R4 and X are as defined above, is obtained by reductive amination between ketone 26 and amine 6 using basically the same conditions as previously described in Scheme 1. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
The compound represented by the above formula I wherein R5 is pyrazole can be prepared by the following synthetic scheme (Scheme 6). Pyrazole compound 29 can be obtained by condensing 1,4-dioxa-8-azaspiro[4.5]decane with 4-fluorobenzonate 28 as previously described in Scheme 1, followed by pyrazole ring formation which can be carried out by reacting with hydrazine. Solvents used in this ring formation include methanol, ethanol, tetrahydrofuran and the like. Ketal hydrolysis under acidic conditions followed by reductive amination, as previously described in Scheme 1, furnishes the final product 31, wherein A, R1, R2, R3, R4 and X are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
The compound represented by the above formula I wherein R5 is acid or ester can be prepared by the following synthetic scheme (Scheme 7). According to one route, 1,4-dioxa-8-azaspiro[4.5]decane is reacted with 4-fluorobenzoate 32 in the presence of base such as pyridine or potassium carbonate to afford ester 33. This reaction can be carried out in a polar solvent such as anhydrous acetonitrile, acetone, dimethylformamide, or pyridine. Acid 35 is obtained via a basic hydrolysis of ester 33. In this reaction lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used as a base, and water or a mixture of water with methanol, ethanol, dioxane and the like can be used as a solvent. Ketal 35 hydrolysis is accomplished in the presence of strong acid such as concentrated hydrochloric acid or 10-30% sulfuric acid. The desired final product (acid 37), wherein A, R2, R2, R3, R4 and X are as defined above, is prepared by utilizing reductive amination of piperidiones 36 with appropriate arylethanolamines or aryloxypropanolamines 6, as previously described in Scheme 1. The corresponding ester 38, wherein A, R1, R2, R3, R4, R6 and X are as defined above (provided that in 38 R6 can not be hydrogen), could be synthesized in the same manner starting with the ester 33 by ketal hydrolysis followed by reductive amination sequence. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
Mono peptide derived from the acid 36 and amino acid and its ester thereof, can be prepared by, for example, the following synthetic scheme(Scheme 8). The carboxylic acid 36 is coupled to the amine nitrogen of amino acid (ester), wherein the amino acid (ester) means the carboxylic acid functionality of the amino acid was protected as an ester. In this amide bond formation process 1,3-dicyclohexylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, diisopropylcarbodiimide, 1,1xe2x80x2-carbonyldiimidazole, 6-chloro-2,4-dimethoxy-1,3,5-triazine and the like can be used as a coupling agent and triethylamine, diisopropylethyl amine, N-methyl morpholine and the like can be used as a base. At this time, as a solvent, methylene chloride, diethyl ether, tetrahydrofuran, dioxane and the like is used. Reductive amination followed by ester hydrolysis, as previously described in Scheme 7, furnishes the desired final product 41, wherein A, R1, R2, R3, R4, X and Aa are as defined above (Scheme 8). A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. The corresponding hydroxamic acid or amide derivative 44, wherein A, R1, R2, R3, R4, R6, R18 (R18 is either R7 or OR7) and X are as defined above, could be synthesized (Scheme 9) in an analogous manner starting with the acid 35 by amide bond formation between acid 35 and amine (NHR6R7) or hydroxylamine (NHR6OR7), followed by ketal hydrolysis and reductive amination, as previously described in Scheme 8. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
Homo analogues (here homo analogues means one carbon chain extended analogues) of compounds 37, 38, 41, 44 can be prepared by, for example, the following synthetic scheme (Scheme 10). 1,4-Dioxa-8-azaspiro[4.5]decane is reacted with 4xe2x80x2-fluoroacetonephenone 45, as previously described in Scheme 1, to give acetonephenone 46. The methyl ketone compound 46 is converted into arylalkanoate 47 using an oxidative rearrangement procedure. In this reaction thallium(ll) nitrate, iodine-silver nitrate and the like is used as an oxidation agent and an alcoholic solvent (R6OH) such as methanol or ethanol is used as a solvent. Ketal and ester hydrolysis followed by reductive amination, as previously described in Scheme 1, generates the desired homo analog 49, wherein A, R1, R2, R3, R4, and X are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. Homo analogues of mono peptide 41 or compound 44 derived from the acid 48 can be prepared in an analogous manner as previously described in Scheme 8 and Scheme 9. 
Two carbon chain extended analogues of compounds 37, 38, 41, 44 can be prepared by, for example, the following synthetic scheme (Scheme 11). Compound 50 can be obtained by a Wittig or related reaction between aldehyde 2 and a Wittig reagent in the presence of a base. In this reaction diethyl ethoxycarbonylmethanephosphonate, (ethoxycarbonylmethyl) triphenylphosphonium chloride, triphenyl(ethoxy-carbonylmethyl)phosphonium bromide and the like can be used as a Wittig reagent and lithium diisopropylamide, sodium hydride, potassium hydroxide and the like can be used as a base. Ketal hydrolysis under acidic conditions followed by reductive amination, as previously described in Scheme 1, generates the desired olefinic analog 52, wherein A, R1, R2, R3, R4, R6, and X are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. The corresponding olefinic acid analog 55, wherein A, R1, R2, R3, R4, and X are as defined above, can be obtained by a basic hydrolysis process. In this case, lithium hydroxide, sodium hydroxide and the like can be used as a base and aqueous methanol, ethanol, tetrahydrofuran and the like can be used as a solvent. The carbon-carbon double bond of compound 52 can be reduced by catalytic hydrogenation in the presence of a metal catalyst such as palladium, platinum, rhodium and the like to give the reduced analog 53, wherein A, R1, R2, R3, R4, R6 and X are as defined above. An alcohol such as methanol, ethanol, isopropanol and the like, acetic acid, tetrahydrofuran, dioxane can be used as solvent in the hydrogenation. The corresponding propanic acid analog 54, wherein A, R1, R2, R3, R4 and X are as defined above, was produced by basic hydrolysis of 53, as previously described in Scheme 7. Alternatively, ester 50 is treated with a base to produce the acid 56, which in turn is treated with a strong acid to remove the protecting ketal group of 56, thus exposing the terminal ketone for a reductive amination process (with hydrogen and catalytic palladium) to generate the same compound 54. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. Mono peptide 41 or compound 44 analogues derived from compound 51 or 57 can be prepared in an analogous manner as previously described in Scheme 8 and Scheme 9. 
Malonic acid analogues of compounds 37, 38, 41, 44 can be prepared as described in Scheme 12 starting from compound 2. A Knoevenagel condensation between a malonic acid diester and the aldehyde 2 yields compound 58. In this reaction sodium acetate, piperidine, piperidineum acetate, pyrrolidine, potassium acetate, sodium carbonate and the like can be used as a base, and an alcohol such as methanol, ethanol, isopropanol, methoxyethanol and the like can be used as a solvent. Ketal hydrolysis followed by reductive amination of piperidione 59 with amine 6, as previously described in Scheme 1, gives the malonic acid analog 60, wherein A, R1, R2, R3, R4, R6 (provided that in 60 R6 can not be hydrogen) and X are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. The diester group in compound 60 could be converted to mono acid or diacid by a basic hydrolysis process, which is well known in the art, to yield compound 61 wherein A, R1, R2, R3, R4, R6 and X are as defined above. Mono peptide 41 or compound 44 analogues derived from compound 59 can be prepared in an analogous manner as previously described in Scheme 8 and Scheme 9. 
Ether analogues of compounds 37, 38, 41, 44 can be prepared by, for example, the following synthetic scheme (Scheme 13). The aldehyde group in compound 2 is reduced by a reducing agent such as sodium borohydride, in an alcoholic solvent, e.g., methanol to yield alcohol 62. Alcohol 62 is alkylated with, for example, iodoacetate sodium salt to generate acid 63, which is then converted to ether analog 65, wherein A, R1, R2, R3, R4 and X are as defined above, using ketal hydrolysis/reductive amination sequence as previously described in Scheme 1. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. Mono peptide 41 and compound 44 analogues derived from compound 64 can be prepared in an analogous manner as previously described in Scheme 8 and Scheme 9. 
Sulfonamide or amide 72 can be conveniently prepared by a variety of methods known in the art. According to one route (Scheme 14), 1,4-dioxa-8-azaspiro[4.5]decane is reacted with 4-nitroarylfluoride 66 in the presence of base such as pyridine or potassium carbonate to afford ketal 67. This reaction can be carried out in a polar solvent such as anhydrous acetonitrile, acetone, dimethylformamide, or pyridine. The nitro group is then reduced by, for example, catalytic hydrogenation to provide aniline 68. The aniline 68 could be acylated with either sulfonyl chlorides or acyl chlorides in the presence of base such as triethylamine or pyridine to give the corresponding acylation product 69. Compound 69 could be optionally alkylated with appropriate alkylating agents (R6-halo) in the presence of base such as potassium carbonate to give the alkylated product 70. Alternatively, a sequence of reductive amination between aniline 68 and appropriate aldehydes or ketones followed by acylation with R9X1Cl furnishes the same alkylated product 70. Ketal hydrolysis followed by reductive amination of piperidiones 71 with amine 6 as previously described in Scheme 1, gives the sulfonamide or amide analog 72, wherein A, X, X1, R1, R2, R3, R4, R6 and R9 are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
Diacylated amine derivatives 78 are also readily prepared by methods known in the literature. For example, as shown in Scheme 15, the hydrochloric salt of 4-piperidone is condensed with 4-nitroarylfluorides, conveniently in pyridine, to give piperidone 74. The nitro group in 74 is then reduced to the corresponding aniline by catalytic hydrogenation as previously described. Diacylation of aniline 75 by R9X1Cl followed by R10X2Cl (R9X1Cl and R10X2Cl could be the same in some cases) gives the desired intermediate 77, which could be converted to the final product 78, wherein A, X, X1, X2, R1, R2, R3, R4, R6, R9 and R10 are as defined above, by a reductive amination process as previously described in Scheme 1. 
Some of the compounds of the present invention are prepared by a novel solution phase methodology (Scheme 16). In this method the product is formed in solution phase reactions and excess reagents are removed from solutions by solid scavenging agents. Treatment of aniline 75 with excess sulfonyl chloride and an resin base such as (piperidineomethyl)polystyrene in a solvent such as dichloromethane or 1,4-dioxane for 1 to 24 hours at room temperature gives the desired sulfonamide 76. The excess sulfonyl chloride is then removed by a nucleophilic scavenging agent, for example, aminomethylated polystyrene resin. The intermediate piperidone 76 could be isolated by filtration and evaporation. The imine formation between the piperidiones and excess arylethanolamines or aryloxypropanolamines is accomplished in a solvent such as methanol and in a water scavenging agent such as trimethyl orthoformate. The imine reduction is achieved by using a solid supported borohydride such as Amberlite IRA-400 borohydride resin. The excess amine is readily removed by quenched with a carboxaldehyde resin such as formylpolystyrene. The final product 79, wherein A, X, X1, R1, R2, R3, R4, R6 and R9 are as defined above, could be purified by the same manner as described in Scheme 1. 
The compounds of the present invention where acidic group R5 is urea can be prepared starting from aniline 73, as shown in Scheme 17. Aniline 80 is available from 73 by treatment of 73 with strong acid such as aqueous concentrated hydrochloric acid. Aniline 80 can be added to isocyanates to give the corresponding substituted urea 81. A reductive amination between amine 6 and 81, as previously described, gives the desired urea 82, wherein A, R1, R2, R3, R4, R6, R7 and X are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
The compounds of the present invention where the cyclic amine is azetidine can be prepared as illustrated in Scheme 18. The alcohol of 83 is protected, for example, as its t-butyldimethylsilyl(TBS) ether to give TBS derivative 84. The protecting diphenylmethyl group in 84 is then removed by trearment of 84 with ammonium formate in the presence of palladium catalyst or raney nickle, typically in refluxing methanol. Condensation of azitidine 85 with arylfluoride 66 as before gives the key intermediate 86. The alcohol of 86 is then converted to the corresponding amine 88 by treatment with mesyl (Ms) chloride followed by benzylamine. The epoxides 89, many of which are commercially available or can be readily prepared as described in Scheme 19, are coupled with amine 88 by heating them neat or in a polar solvent. Preferably, the reaction is carried under refluxing methanol. The nitro group in 90 is then reduced, for example, by sodium hydrosulfite, to give an aniline. The aniline is then acylated with sulfonyl chloride, acyl chloride or isocyanates followed by deprotection of benzyl group with ammonium formate/palladium on carbon to give the desired azitidine 92, wherein A, R1, R2, R3, R4, R9 and X1 are as defined above. A salt is optionally produced by the addition of an acid or base, such as hydrogen chloride gas or hydrochloric acid. 
Many of arylethanolamines or aryloxypropanolamines 6 are commercially available or readily prepared by known methods [1. Guy, A., Ferroud, D. C., Garreay, R., Godefroy-Falguieres A. Synthesis, 1992, 821; 2. Leclerc, G., Bizec, J. C. J. Med. Chem., 1980, 23, 738; 3. Tominaga, M., Ogawa, H., Yo, E., Yamashita, S., Yabuuchi, Y., Nakagawa, K. Chem. Pharm. Bull. 1987, 35, 3699]. In one route (Scheme 19) equimolecular amounts of alcohol 93 and enantiomerically pure (2S)-glycidyl 3-nitrobenzene sulfonate 94 are dissolved in an organic solvent such as acetone or N,N-dimethylformamide and treated with a base such as sodium hydride or potassium carbonate for 0.5 to 24 hours at a temperature of 20-100xc2x0 C. to provide oxirane 89. The oxirane 89 is converted to the corresponding amine 97 or 98, wherein A, R1, R2, and R3 are as defined above (provided that in 98 R1, R2, and R3 can not be benzyloxy), by regioselective ring opening of oxirane 89 with either lithium azide in a solvent such as hexamethylphosphoramide (HMPA) followed by reduction with, for example, triphenylphosphine in aqueous tetrahydrofuran, or with one equivalent of dibenzylamine followed by ammonium formate/palladium on carbon reduction. The other enantiomer is available through an analogous preparative sequence with the corresponding (2R)-glycidyl 3-nitrobenzene sulfonate. 
One route to the desired arylethanolamines 6 is illustrated in Scheme 20. Methylketones 99 are all available commercially or can be prepared by conventional methods disclosed in the art. Compound 99 can be easily converted to the corresponding xcex1-haloketone 100, wherein halo is chlorine, bromine or iodine, using well known halogenation agents such as chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide and the like. The resultant xcex1-haloketone 100 is then reduced, for example, by sodium borohydride, to give the corresponding racemic alcohol 101. An enantiomerically enriched alcohol 101 may be prepared by asymmetric reduction of xcex1-haloketone 100 with chiral reducing agents such as (+) or (xe2x88x92)-B-chlorodiisopinocampheylborane (DIP-Cl), R or S-Alpine borane, cis-(1R, 2S) or cis (1S, 2R)-oxazaborolidine and the like. The alcohol of intermediate 101 may be protected, for example, as its triethylsilyl ether. In some cases, however, the alcohol protecting group is not required. The halo compound 101 can be easily converted to the corresponding benzylamine 102 by heating to 30-80xc2x0 C. with large excess of benzylamine neat or as a solution in a polar solvent such as tetrahydrofuran, acetonitrile or methanol for 1 to 24 hours. The protecting group is then removed, in the case of silyl ether, by treatment of 102 with a fluoride agent such as tetrabutylammonium fluoride (TBAF). Compound 103 is then subjected to catalytic hydrogenation in the presence of ammonium formate/Pd to give the desired aminoethanol 104, wherein A, R1, R2 and R3 are as defined above. The reduction is conveniently conducted in refluxing methanol in the presence of a large excess of ammonium formate.
Alternatively, the halo compound 101 could be converted to the corresponding amine 104 by either treatment with a sodium azide/sodium iodide mixture in a polar solvent such as dimethyl sulfoxide, hexamethylphosphoramide and the like followed by catalytic hydrogenation in the presence of a metal catalyst such as palladium, platinum and the like; or treatment with a base such as sodium hydroxide, potassium carbonate or the like followed by ammonia in a polar solvent such as methanol, tetrahydrofuran or the like. 
The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was confirmed with representative compounds of this invention in the following standard pharmacological test procedures, which measured the binding selectivity to the xcex21, xcex22, and xcex23 adrenergic receptors. Binding to the receptors was measured in Chinese Hamster ovary (CHO) cells that were transfected with adrenergic receptors. The following briefly summarizes the procedure used and results obtained.
Transfection of CHO cells with xcex21 and xcex22 adrenergic receptors: CHO cells were transfected with human xcex21- or xcex22-adrenergic receptors as described in Tate, K. M., , Eur. J. Biochem., 196:357-361 (1991).
Cloning of Human xcex23-AR Genomic DNA: cDNA was constructed by ligating four polymerase chain reaction (PCR) products using the following primers: an ATG-Narl fragment, sense primer 5xe2x80x2-CTTCCCTACCGCCCCACGCGCGATC3xe2x80x2 and anti-sense primer 5xe2x80x2CTGGCGCCCAACGGCCAGTGGCCAGTC3xe2x80x2; a Narl-Accl fragment, 5xe2x80x2TTGGCGCTGATGGCCACTGGCCGTTTG3xe2x80x2 as sense and 5xe2x80x2GCGCGTAGACGAAGAGCATCACGAG3xe2x80x2 as anti-sense primer; an Accli-Styl fragment, sense primer 5xe2x80x2CTCGTGATGCTCTTCGTCTCACGCGC3xe2x80x2 and anti-sense primer 5xe2x80x2GTGAAGGTGCCCATGATGAGACCCAAGG3xe2x80x2 and a Styl-TAG fragment, with sense primer 5xe2x80x2CCCTGTGCACCTTGGGTCTCATCATGG3xe2x80x2 and anti-sense primer 5xe2x80x2CCTCTGCCCCGGTTACCTACCC3xe2x80x2. The corresponding primer sequences are described in Mantzoros, C. S., etal., Diabetes 45: 909-914 (1996). The four fragments are ligated into a pUC 18 plasmid (Gibco-BRL) and sequenced. Full length xcex23 AR clones (402 amino acids) containing the last 6 amino acids of hxcex23-AR are prepared with the xcex23-xcex2ARpcDNA3 from ATTC.
Binding Procedure: Clones expressing receptor levels of 70 to 110 fmoles/mg protein were used in the test procedures. CHO cells were grown in 24-well tissue culture plates in Dulbecco""s Modified Eagle Media with 10% fetal bovine serum, MEM non-essential amino acids, Penicillin-Streptompycin and Geneticin. On the day of test procedure, growth medium was replaced with preincubation media (Dulbecco""s Modified Eagle Media) and incubated for 30 minutes at 37xc2x0 C. Preincubation medium was replaced with 0.2 ml treatment medium containing DMEM media containing 250 xcexcM IBMX (isobutyl-1-methylxantine) plus 1 mM ascorbic acid with test compound dissolved in DMSO. Test compounds were tested over a concentration range of 10xe2x88x929 M to 10xe2x88x925 M for xcex23 cells and 10xe2x88x928 to 10xe2x88x924 M for xcex21 and xcex22 transfected cells. Isoproterenol (10xe2x88x925 M) was used as an internal standard for comparison of activity. Cells were incubated at 37xc2x0 C. on a rocker for 30 min with the xcex23 cells and 15 min for xcex21 and xcex22 cells. Incubation was stopped with the addition of 0.2N HCl and neutralized with 2.5N NaOH. The plates, containing the cells and neutralized media, were stored at xe2x88x9220 degrees celsius until ready to test for cAMP using the SPA test kit (Amersham).
Data Analysis and Results: Data collected from the SPA test procedure were analyzed as per cent of the maximal isoproterenol response at 10xe2x88x925 M. Activity curves were plotted using the SAS statistical and graphics software. EC50 values were generated for each compound and the maximal response (IA) developed for each compound is compared to the maximal response of isoproternol at 10xe2x88x925 M from the following formula: 
Table I shows the xcex23-adronergic receptor EC50 and IA values for the representative compounds of this invention that were evaluated in this standard pharmacological test procedure. These results show that compounds of the present invention have activity at the xcex23-adrenergic receptor. The compounds of this inventon had weaker or no activity at xcex21 and/or xcex22-adrenergic receptor.
Evaluation in xcex23 Knockout(KO) and xcex23 Transgenic(Tg) Mice: The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was also confirmed with representative compounds of this invention in an in vivo standard pharmacoligical test procedure which compared thermogenesis in transgenic mice (Tg mice) and xcex23-knockout mice (KO mice). The procedure used and results obtained and provided below.
xcex23-Adrenergic receptor knockout mice and xcex23 human transgenic mice are created on an inbred FVB background (Susulic, V. S., et.al., J. Biol. Chem., 1995, 270 (49), 29483-29492). Female FVB xcex23 transgenic and xcex23 knockout mice were used to determine in vivo activity and selectivity of xcex23 agonists. Compounds selected for in vivo testing had xcex23 EC50 less than 30 nm and were full agonists in CHO cells expressing human xcex23 receptors. These compounds were also selective in being 100-fold less responsive and partial agonists when tested in xcex21 and xcex22 transfected CHO cells. Compounds were tested for increased thermogenesis using the Oxymax indirect calorimeter (Columbus Instruments, Columbus, Ohio). Fed animals were placed in chambers for 3 hours to obtain baseline O2 and CO2 values. Eight fed mice were weighed in pairs and placed in 4 chambers, two per chamber. The relative gas content of each chamber was sampled and recorded at 10 to 12 minute intervals. For each sample, energy expenditure values were calculated by the Oxymax and expressed as kcal/hr. After 3 hours of baseline measurement, the mice were removed, treated and replaced in the chambers. The xcex23 agonists were injected at doses between 0.1 and 20 mg/kg i.p. and between 1.0 and 30 mg/kg for oral administration. Compounds in 10 mM or 10 mg/ml DMSO solutions were suspended in 0.5% methylcellulose: 0.1% tween-80 and injected i.p. or administered by oral gavage. Some compounds were suspended in 5.0% tween-80 for oral administration. Post-treatment kcal/hr values were taken between 40 minutes and 2.5 hours later. The 6 to 10 sample sections of the pre-treatment and post-treatment periods, which appear to best represent stable resting thermogenesis, were selected. Each of these sample values was corrected for body weight and used such that each pair of mice serves as its own baseline for both T test and percent increase in thermogenesis calculations. An ANOVA and a one sided T test (H1: Post greater than Pre) are performed using the SAS software modified to down weight extreme values. In a separate set of calculations, values that appear to be too high to represent resting thermogenesis are discarded (activity monitor sampling associated spikes in thermogenesis with ambulatory activity). The mean baseline value for each chamber is subtracted from mean post-treatment value for that chamber. This baseline-subtracted value is divided by the mean baseline value and multiplied by 100 to obtain a percent increase in thermogenesis for each chamber. The combined mean percent increase, standard deviation, and standard error of the mean for each chamber is calculated. Compounds were considered active if they were able to produce a statistically significant 15% increase in thermogenesis in xcex23 transgenic mice and no significant increase in xcex23 knockout mice. The results are shown in the table below.
Based on the results obtained in these standard pharmacological test procedures, representative compounds of this invention have been shown to be selective xcex23 adrenergic receptor agonists and are therefore useful in treating metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
As used in accordance with this invention, the term providing an effective amount means either directly administering such a compound of this invention, or administering a prodrug, derivative, or analog which will form an effective amount of the compound of this invention within the body.
It is understood that the effective dosage of the active compounds of this invention may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. As used in accordance with invention, satisfactory results may be obtained when the compounds of this invention are administered to the individual in need at a daily dosage of from about 0.1 mg to about 1 mg per kilogram of body weight, preferably administered in divided doses two to six times per day, or in a sustained release form. For most large mammals, the total daily dosage is from about 3.5 mg to about 140 mg. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
Such doses may be administered in any manner useful in directing the active compounds herein to the recipient""s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, intranasally, vaginally, and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectals and vaginal).
Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccol forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disentegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthum gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.
The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository""s melting point, and glycerin, Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
The compounds of the present invention also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.
Animal feed compositions effective for increasing lean meat deposition and for improving lean meat to fat ratio in poultry, swine, sheep, goats, and cattle are generally prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide from about 1 to 1000 ppm of the compound in the feed. Animal feed supplements can be prepared by admixing about 75% to 95% by weight of a compound of the present invention with about 5% to about 25% by weight of a suitable carrier or diluent. Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, sodium chloride, cornmeal, cane molasses, urea, bone meal, corncob meal and the like. The carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended. It thus performs an important function by ensuring proper distribution of the active ingredient throughout the feed. The supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
The preferred medicated swine, cattle, sheep and goat feed generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed. The preferred poultry and domestic pet feed usually contain about 0.01 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.
For parenteral administration the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought. In general, parenteral administration involves injection of a sufficient amount of the compounds of the present invention to provide the animal with 0.001 to 100 mg/kg/day of body weight of the active ingredient. The preferred dosage for swine, cattle, sheep and goats is in the range of from 0.001 to 50 mg/kg/day of body weight of active ingredient; whereas, the preferred dose level for poultry and domestic pets is usually in the range of from 0.001 to 35 mg/kg/day of body weight.
Paste formulations can be prepared by dispersing the active compounds in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like. Pellets containing an effective amount of the compounds of the present invention can be prepared by admixing the compounds of the present invention with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process. It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal""s body. For the poultry and swine raisers, using the method of the present invention yields leaner animals.
Additionally, the compounds of this invention are useful in increasing the lean mass to fat ratio in domestic pets, for the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the present invention provides the means by which this can be accomplished.
The following procedures describe the preparation of representative compounds of this invention.